This invention is in the area of organic chemistry, and specifically relates to new piperidinedione derivatives with cytostatic properties.
A tumor is an unregulated, disorganized proliferation of cell growth. A tumor is malignant, or cancerous, if it has the properties of invasiveness and metastasis. Invasiveness refers to the tendency of a tumor to enter surrounding tissue, breaking through the basal laminas that define the boundaries of the tissues, thereby often entering the body's circulatory system. Metastasis refers to the tendency of a tumor to migrate to other areas of the body and establish areas of proliferation away from the site of initial appearance.
Cancer is now the second leading cause of death in the United States, Europe, and Japan, resulting in approximately 1,000,000 deaths annually in these countries. In the United States alone, each year over one million people are diagnosed with cancer, and over 500,000 people die from the disease. The number of newly diagnosed cancerous growths in patients in the United States is growing at a rate of 3% a year.
Cancer is not fully understood on the molecular level. It is known that exposure of a cell to a carcinogen such as certain viruses, certain chemicals, or radiation, leads to DNA alteration that activates han "oncogene." Oncogenes are initially normal genes (called prooncogenes) that by mutation or altered context of expression become transforming genes. The products of transforming genes cause inappropriate cell growth. More than twenty different normal cellular genes can become oncogenes by genetic alteration. Transformed cells differ from normal cells in many ways, including cell morphology, cell-to-cell interactions, membrane content, cytoskeletal structure, protein secretion, gene expression and mortality (transformed cells can grow indefinitely).
All of the various cell types of the body can be transformed into malignant cells. The most frequent tumor site is lung, followed by colorectal, breast, prostate, bladder, pancreas, and then ovary.
Cancer is now treated with one or a combination of three types of therapies: surgery, radiation, and chemotherapy Surgery involves the bulk removal of diseased tissue. While surgery is sometimes effective in removing tumors located at certain sites, for example, in the breast, colon, and skin, it cannot be used in the treatment of tumors located in other areas, such as the backbone, nor in the treatment of disseminated neoplastic conditions such as leukemia.
Chemotherapy now represents less than 4% of the total expenditures on the treatment of cancer. Chemotherapy involves the disruption of cell replication or cell metabolism. It is used most often in the treatment of leukemia and breast, lung, and testicular cancer.
There are four major classes of chemotherapeutic agents currently in use for the treatment of cancer; anthracyclines, alkylating agents, antiproliferatives, and hormonal agents. A variety of methods exist to attempt to identify new antineoplastic chemotherapeutic agents, including random screening of compounds, preparation of analogs of active compounds, computer or physical modeling, and combinations of these techniques. None of these methods, however, have yet identified the optimal chemotherapeutic agent for neoplastic diseases. U.S. Pat. No. 4,461,619 to Hendry et al., discloses a method to determine the relationship of chemical structure to biological activity based on the topology and physicochemical properties of "cavities" or "artificial constructs" in double stranded DNA, double stranded RNA, or double stranded DNA-RNA. While modeling can be very helpful in chemotherapy research, it cannot predict whether a target compound will pass through the cell wall, whether it is stable in vivo generally or in the cytoplasm specifically, or whether the therapeutic index is appropriate for clinical use of the drug.
Burzynski has proposed that the human organism is equipped with a corrective system that can reprogram the growth of newly developed neoplastic cells to transform them back into normal cells. He has isolated a number of medium sized peptides, referred to as antineoplastons, that are produced by the body to protect it against the development of neoplastic growth by a nonimmunological process that does not significantly inhibit the growth of normal tissue. The most potent antineoplaston isolated by Burzynski is 3-[N-phenylacetylaminopiperidine]-2,6-dione (referred to below as A10). Antineoplastons are described in U.S. Pat. No. 4,444,890, entitled "Testing Procedure to Aid Diagnosis of Cancer and Evaluate the Progress of Cancer Therapy"; U.S. Pat. No. 4,593,038, entitled "Topical Use of 3-Phenylacetylamino-2,6-Piperidinedione for Treatment of Skin Wrinkles and Hyperpigmentation"; and U.S. Pat. Nos. 4,558,057, 4,559,325 and 4,470,970, entitled "Purified Antineoplaston Fractions and Methods of Treating Neoplastic Disease." According to these patents, administration of antineoplastons to cancer patients has resulted in symptomatic improvement in 93% of the patients treated. A remission of the tumor was noted in about 45% of the patients
The initial hydrolysis product and biological degradation product of A10 is phenylacetylglutamine, which is produced in vivo from phenylacetic acid and glutamine. In fact, A10 may be cyclized from phenylacetylglutamine in vivo. Markaverich, et al., report that a compound structurally related to phenylacetic acid, methyl p-hydroxyphenylacetate, inhibits MCF-7 human breast cancer cells in vitro. Markaverich, et al., J. of Biol. Chem. 263(15), 7203 (1988).
Hendry has shown that A10 fits in a stereochemical manner between base pairs of double stranded DNA. Hendry, L.B., et al., "Modeling Studies Suggest the Modified Dipeptide Analog Phenylacetylamino-2,6-piperidinedione may interact with DNA," Advances in Experimental and Clinical Chemotheraoy. 15th International Congress of Chemotherapy, Istanbul, Turkey, 1987. Specifically, A10 is capable of forming a stereospecific hydrogen bond between the imino proton of the piperidinedione ring and the phosphate oxygen on the DNA backbone. A10 does not bind covalently to DNA, which may explain why the compound is cytostatic and not cytotoxic. The acute toxicity of A10 in mice is between 1.35 and 10.33 g/kg. AIO has been administered without serious side effects at a dosage of up to 10 grams per day to humans suffering from cancer.
While A10 is a useful drug in the treatment o neoplastic diseases, there is a need for new cytostatic agents that may be more effective in stimulating tumor remission, and that may be effective when administered in lower dosages. The tragic number of deaths that occur each year from this disease accentuates the urgency of this need.
In light of the above, it is clear that there is a strong need for new cytostatic agents that can effectively insert stereochemically into DNA.
Therefore, it is an object of the present invention to provide a compound that has a cytostatic effect on cancer cells.
It is a further object of the present invention to provide a compound that can insert stereochemically into DNA.